1. Field of the Invention
The present invention relates to the topical treatment of cutaneous virus infections. It relates particularly to the topical treatment of herpes simplex infections, including herpes simplex types 1 and 2, using formulations comprising phosphate esters of anti-herpes antiviral nucleoside analogues such as acyclovir.
2. Background of the Art
Acyclovir (ACV) is an antiviral nucleoside analogue of guanosine which contains an unusual incomplete (acyclic) sugar moiety. Nucleoside analogues interrupt the process of DNA replication in cells, and are for that reason useful as antiviral and antineoplastic agents. ACV is particularly effective in treating herpes simplex virus infections of types I and II. The antiherpes virus activity of ACV in cells occurs with low toxicity because ACV is selectively phosphorylated by HSV thymidine kinase, but not host cell thymidine kinase. As a consequence, only cells infected with HSV can form ACV monophosphate (ACV-MP). ACV-MP is then anabolically converted by cellular enzymes to ACV triphosphate, the active agent that interferes with viral replication. (Fyfe, J., et al., J. Biol. Chem. 253:8721-8727 (1978); Furman, P., et al., J. Virol. 32:72-77 (1979)).
The anti-herpes virus activity of acyclovir has been demonstrated in inhibiting the replication of herpes simplex virus in tissue culture cells (O'Brien, W., et al., Antimicrob. Agents and Chemother. 34:1178-1182 (1990); it has also been demonstrated in clinical studies wherein patients infected with HSV were treated with orally administered ACV (Whitley, R., Immunobiol. and Prophylaxis of Human Herpesvirus Infections, C. Lopez et al, (eds) Plenum Press, NY 1990; and Straus, S., Sexually Transmitted Diseases 16(2):107-113 (1989).
Acyclovir is the treatment of choice for mucosal and cutaneous HSV infections, although patients receiving topical acyclovir therapy experience some reductions of their symptoms, healing is slow and incomplete (Spruance, S., et al., J. Infect. Dis. 146:85-90 (1982); and Spruance, S., et al., Antimicrob. Agents Chemother. 25:553-555 (1984).
Combination treatment using ACV together with interferon for herpes virus infected cultured cells (O'Brien, W., et al., Antimicrob. Agents and Chemother. 34(6):1178-1182 (1990) or using ACV together with A1110U, an HSV inactivator, as a topical therapy for herpetic keratitis in athymic mice (Lobe, D., et al., Antiviral Research 15:87-100 (1991) showed synergistic antiherpesvirus I activity over the use of ACV alone.
Acyclovir has been used with qualified success in a clinical trial to treat another viral disease, varicella (chickenpox) (Whitley, R., et al., Immunobiology and Prophylaxis of Human Herpesvirus Infections, C. Lopez (ed), Plenum Press, New York (1990) pp. 243-253. It has also been used experimentally but without success in treating other disorders in which a viral etiology was hypothesized, such as aplastic anemia (Gomez-Almaguer, D., et al. Amer. J. of Hematology 29:172-173 (1988) and duodenal ulcer (Rune, S. J., et al., Gut 31:151-152 (1990)).
Acyclovir phosphates have been shown to be efficacious against wild type or laboratory isolates of HSV-1 infected cultured cells in vitro, but have little or no efficacy against thymidine kinase defective mutants of HSV under the same conditions. (See data of FIGS. 1 and 2).
In immunosuppressed patients, such as those with HIV (AIDS) infections or transplant recipients who are taking immunosuppressive drugs to prevent transplant rejection, ACV has been given chronically to prevent troublesome outbreaks of herpes. Such therapy provides a selective pressure which leads to mutations in HSV thymidine kinase (90% frequency) as well as DNA polymerase (10% frequency), which in turn results in ACV-resistant viral strains. There is no effective topical therapy for these acyclovir resistant herpes virus strains.